Painful neuropathy is the principal dose-limiting factor in chemotherapy with vincristine, bortezomib, and thalidomide. This pain is refractory to treatment and often persists in cancer survivors. The long-term goal of this project is to determine the mechanism of chemotherapy-induced pain and identify potential therapeutic interventions for its relief and prevention. Several key tenets of a working model of chemoneuropathy will be tested in three specific aims conducted in humans who are undergoing chemotherapy for multiple myeloma or acute leukemia and/or in tumor-free animals treated with one of the same compounds. Specific Aim i will test the hypothesis that vincristine, bortezomib and thalidomide induce or unmask elevated levels of proinflammatory cytokines and increased levels of activated NF-KB. Specific Aim 2 will test the hypothesis that vincristine, bortezomib and thalidomide have shared effects on primary afferent fibers leading to neuropathic pain. Specific Aim 3 will test the hypothesis that chemotherapy-induced neuropathy is produced by the action of pro-inflammatory cytokines in specific body compartments. This will be tested in humans and animals. In summary this project will define mechanisms of chemotherapy-induced pain, identify near-term treatment candidates, and establish the key databases needed to design and justify clinical trials that will be the subject of follow-up studies. This project will provide direct evidence for several important basic tenets of a pathophysiological model of chemo-neuropathy that in turn will define important new targets for therapy and intervention. This project will therefore impact on the quality of life, survival and the return to productivity of nearly all cancer patients who receive vincristine, thalidomide or bortezomib.